17-carboxyalkylated 3-oxygenated 6-methylandrosten-17-ol lactones and intermediates



2,938,031 Patented May 24, 1 960 ice alkylated androst--ene-3fl,lip-diol of lactonic formula 2,938,031 17-CARBOXYALKYLATED 3-0XYGENATED on. 1

NIETHYLANDROSTEN-17-OL LACTONES AND 5 NTERMEDIATES Roy H. Bible, In, Morton Grove, and Robert R. Burtncr,

Skokie, 11]., assignors to G. D. Searle & Co., Chicago,

111., a corporation of Delaware No Drawing. Filed Dec. 11, 1958, Ser. No. 779,531 H0 10 Claims is reduced with lithium aluminum hydride to the corresponding triol, which is di esterified (the l 7fi-hydroxyl This invention relates to l7 cal.boxyalkylated 15 being sterically hindered) to increase solubllity and then genated 6-methylandrosten-17-ol lactones and processes coPverted to derivative with perPenzoic for the manufacture thereof. More particularly, this inepoxlde nng the lmkages vention relates to latones f the formula cleaved Wlth methylmagnesium bromide to give the 6- methyl-3B,5ot,l7p,w-tetraol, which lactonizes on chromic acid oxidation of the side chain hydroxyl to carboxyl.

From the resultant material, the elements of water in the 5 and 6 positions are removed by heating with finelydivided (ZOO-mesh) magnesia-silica gel in a solvent medium. The 6p-methyl-3-oxo products of the invention thus obtained CHI Z =0 on, :1

wherein Z is an alkylene or alkenylene rad1cal, X is a carbonyl or hydroxymethylene radical, the 6-methyl substituent is either a or B, and-as will be apparent from the dotted line in rings A and Bthere is a 4(5) or 5(6) double bond present. Among the radicals contemplated O: by Z in the formula, those which contribute at least 2 and fewer than 4 carbon atoms are preferred. Examples of i such radicals are ethylene, vinylene, trimethylene, and are Converted f Y '0 Y- fi- Y Products propenylene groupings, and radicals derived therefrom hereof y l'eductlon W pq yq by the replacement of hydrogen therein with 1 or more 40 The y -5- l 0f thls mvfifntlon can be manulower alkyl groupings. factured as follows: An appropriate 17a-alkynyl-6- Equivalent to the foregoing lactones for purposes of mEthYIaBdIOSt-5'eIIe'3fl,17541331 this invention are the corresponding hydroxy acids and CHI their alkali salts, of the formula CH (9H,)..CECH

CH: OH CH: z -o o OM 5 p HO derived by condensation of 3B-hydroxy-6-methylandrost-5 wh re1n X and Z a d fi d s before n M is y g en-17-one with acetylene or propargyl bromide, i cona alkall metal, me amlflmllum Tadlcalverted to the corresponding l7ot-carboxyalkynyl com- T a t s. y y aclds, and salts hereinabove pound by seriatim treatment with the Grignard reagent crrbed are useful because of ei a e Pharand carbon dioxide. Selective hydrogenation of the acid macological properties. For example, they are unusually h b i d fi -d h 3 g-hyd gxy-fi-methyl products Potent diuretics, esp y adapted to block the Effect Of aforesaid, those wherein Z is an alkenylene radical being desoxycorticosterone acetate on urinary sodium and potasproduced when the hydrogenation is conducted in the siurn. It follows that the intermediates from which these presence of a catalyst of the order of activity of palladium diuretic products can be obtained are also useful. supported on calcium carbonate, and those wherein Z is The 6,9-methyl compounds of this invention can be saturated resulting from the use of a more active catalyst manufactured as follows: An appropriate 17a-carboxysuch as palladium on charcoal.

,3; The 6a-methyl-3-oxo products of this invention can be CHa Z CH3 i by reductionwith sodium borohydride.

" Those skilled in the art will readily appreciate that the 7 described lactones, on contact with aqueous alkali, are converted to salts of the corresponding hydroxy acids, from which the free acids can be obtained by a critically brief exposure to a proton source. Prolongation of the exposure time induces lactonization.

The following examples describe in detail certain of I the compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be ap parent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the pur pose and intent of this disclosure. In the examples hereinafter detailed, temperatures are given in degrees centigrade, pressures in pounds per square inch, and relative amounts of materials in parts by weight, except as otherwise noted.

Example 1 3 8,175 dihy'droxy 17a-(3-hydroxypropyl)androst-S- ene.A mixture of 30 parts of lithium aluminum hydride and 700 parts of peroxide-free tetrahydrofuran is vigorously agitated for 1 hour, following which a solution of 82 parts of l7a-(2-carboxyethyl)androst-5-ene-3,B,175- diol lactone in 360 parts of tetrahydrofuran is added during 2% hours with continued agitation. Agitation is maintained while the resulting. mixture is heated at the boiling point under reflux for 16 hours and then successively and cautiously is diluted with 180 parts of ethyl acetate, 200 parts of water, and 1000 parts of 10% hydrochloric acid. The solid which precipitates is collected and purified by successive trituration with 1500 parts of chloroform, 750 parts of chloroform, 800 parts of methanol, and 750 parts of chloroform. The resultant product is stripped of residual solvent by drying at 65 Infrared analysis of this material'in a potassium bromide disc shows no absorption in the 5-6; region, confirming reduction of the carbonyl group in the starting lactone. The product thus obtained 36,175-dihydroxy-17a-(3- hydroxypropyl)androst-S-ene, of the formula Example 2 "3fl-acetoxy 17o: (3-acetoxypropyl)androst-S-en-I75- ol;'A mixture of 81 parts of 3,3,175-dihydroxy-17a-(3- hydroxypropyl)androst-S-ene, 560 parts of pyridine, and 96 parts of acetic anhydride is heated at for 30 minutes and then filtered hot. The'filtrate is poured into 3000 parts of hot water, precipitating a granular solid which is collected and washed with water, This solid is 3j3-acetoxy-17ot-(3-acetoxypropyl)androst-S-en- -01 which, dried at 65 for 18 hours, is adapted to use in the procedure of Example 3 hereinafter without further processing. The product has the formula OH: CH3 cmomomooocre Example 3 3B acetoxy-17a-(3-acetoxypropyl)-5a,6a-epoxyandrostan-17B-0L-A solution of 69 parts of perbenzoic acid in approximately 850 parts of benzene is added over a period of 5 minutes to a solution of 198 parts of 3dacetoxy 17oz (3-acetoxypropyl)androst-5-en 17B-0l in 1350 parts of benzene. .There'sultant mixture is vigorously agitated and then let stand for 3 hours. his next washed with aqueous 5% sodium carbonate and, finally, with water, the latter operation being continued'untilthe washings are neutral. Solvent is removed by distillation, and the residue is purified by recrystallization from a mixture of chloroform and hexane." 3fl-acetoxy-17a-(3- acetoxypropyl)5u,6ot-epoxyandrostan-1718431 is obtained thus in the form' of platelets melting at 1405-1425". The product shows a specific rotation of 68, and has the formula CHa' H oniomctnoooorn' GHaGO O l b Example 4 3;s,5a,17p trihydr0xy-17a (3-hydroxypropyD-6B methylandrostane.A solution of approximately 30 parts of 3B-acetoxy-17a-(3-acetoxypropyl)-Su,6m-epoxyandro- Si3l1-17fl-01 in parts of peroxide-free tetrahydrofuran is slowly added, with agitation, toa mixture of 286 parts of methylmagnesium bromide and 560 parts of arihydrous ether. The resultant mixture is freed of ether by distillation to a vapor temperature of 59 and then heated at the boiling point under reflux for 18 hours, agitation being maintainedthroughoutr The mixture is thereupon chilled and poured .onto ZOOO pai-ts of ice. The resultant mixture, in turn, is extracted with dichloro- CHiCHaGHaOH 17a(2-carb0xyethyl)-5a,17}8 dihydroxy 6fl-methylandroszan-3-one lactone.To a mixture of 96 parts of 3fi,5a,l7;3 trihydroxy-17a-(3-hydroxypropyl)-6B-methylandrostane in 4000 parts of acetone is cautiously added, with vigorous agitation, a solution of 94 parts of chromium trioxide and 148 parts of concentrated sulfuric acid in 350 parts of water. Agitation is continued for 3 minutes after the addition is complete, at which point excess chromium trioxide is decomposed by the addition of 240 parts of 2-propanol. The mixture is then poured into a large volume of water, and the solid which precipitates is collected on a filter. The material thus obtained is 17m (2 carboxyethyl)-5a,17[3-dihydroxy-6B- methylandrostan-3-one lactone which, recrystallized from methanol, is obtained as platelets melting in the range 237-242. The product has a specific rotation of .2 5 and is characterized by peaks in the infrared spectrum at 5.65, 5.83, and 10.84 The product has the formula cut Ha Example 6 17a (Z-carboxyethyl) -17;8-hydroxy-GB-methylandrost- 4-en-3-one lactne.A solution of 2 parts of 170M2- carboxyethyl) 5a,17/3-dihydroxy-6B-methylandrostan-3r one lactone in 360 parts of benzene is heated at the boiling point with agitation under reflux in the presence or" 20 parts of 200-mesh magnesia-silica gel for 4 hours. (The latter material is marketed under the trade name Florisil.) The gel is then filtered out and washed with ethyl acetate, and the resultant filtrate and washings are combined and stripped of solvent by vacuum distillation. The residue is a crystalline solid which recrystallizes from aqueous acetone as a feather-like material melting at l89.5-19l.5. This material is l7ot-(2-carboxyethyn- 17fi-hydroxy-6,8-methylandrost-4-en-3-one lactone. It shows a specific rotation of +21 and has the formula CH: H30" Example 7 17a; 2 carboxyethyl)-6B-methylandrost-4-ens-313, 175-dial lactone.-A solution of 5 parts of sodium bOI'O? hydride in 200 parts of 95% ethanol is added to a solution of 6 parts of 17a-(2-carboxyethyl)-17fl-hydroxy-6B- methylandrost-4-en-3-one lactone in 70 0 parts of 95% ethanol. The resultant mixture is let stand for 45 minutes, whereupon unreacted borohydride is decomposed by cautious addition of a solution of 80 parts of acetic acid in 300 parts of water. The mixture is concentrated to about /2 volume by distillation and then diluted'with approximately 3990 parts of water. The solid which separates on standing is filtered oil and dried. The material thus obtained is the desired 17a-(2-carboxyethyl)- 6,8-methlandrost-4-ene-3{3,175-dial lactone, which is characterized by absorption bands in the infrared at 5.66 and 2.75 No appreciable absorption in the ultraviolet region from 200 to 300 m is observed. The product has the formula Example 8 17u-.carboxyethynyl 6 methylandrost- S-ene-Sfi, 17B-di0l.--A solution of approximately 25 parts of 17aethynyl-6-methylandrost-5-ene-3B,17 3-diol [described by Grenville et al., J. Chem. Soc., 1957, 4111] in 225 parts of tetrahydrofuran is added with agitation during a 10 minute period to a solution of 89 parts of methylmagnesium bromide in 175 parts of ether diluted with 630 parts of tetrahydrofuran. Agitation is maintained for 20 hours while the reaction mixture is heated at the boiling point under reflux, whereupon carbonation of the Grignard complex thus produced is achieved by continued and vigorous agitation for 24 hours under an atmosphere of carbon dioxide. The resultant gray suspension is poured into an ice-oold solution of 98 parts of sulfuric acid in 1500 parts of water, at which point solvent is removed by vacuum distillation. Insoluble solids are collected on a filter, rinsed free of mineral acid with water, and dried. The product thus obtained is the desired 17 carboxyethynyl-6-rnethylandrost-5-ene-3B,17,6-diol, which is further purified by suspending for 5 minutes in parts of boiling chloroform, filtering hot, and rinsing with two 40-part portions of boiling chloroform. The

PEG O OH Example 9 A. 17a (2 carboxyethyl) 6 methylandrost ene-3fl,17p-di0l.A solution of 373 parts of l7a-carboxyethynyl-6-methylandrost-5-ene-3p,17fi-diol in 4400 parts of anhydrous ethanol containing 102 parts of triethylamine is hydrogenated at 45 p.s.i. in the presence of 37 parts of 5% palladium on charcoal catalyst until 4 parts of hydrogen is absorbed. The mixture is then filtered and the filtrate is concentrated to $5 volume by vacuum distillation. The residual solution is poured into 17,300 parts of water containing 308 parts of concentrated hydrochloric acid. The finely-divided white solid which precipitates is collected on a filter, washed thereon with water, and dried. This material is the desired 17a (2 carboxyethyl) 6 methylandrost 5 ene 3ft,l7}3-diol, which melts in the range 160-170" with loss of water. The product has the formula CH3 CH cniomooon 50H B. 17a (2 carboxyethyl) 6 methylandrost 5 ate-3,8,1 7 8-di0l lactone.To a suspension of 25 parts of the hydroxy acid of the preceding part A of this example in 80 parts of methanol is added 10 parts of a 10% solution of hydrogen chloride. The solid dissolves in about 3 minutes, and the resultant solution is thereupon immediately poured into 1000 parts of water. The desired lactone precipitates as a tacky material which is collected on a filter, rinsed thereon with water, and dried. Crystallization from a mixture of ethyl acetate and isopropyl ether aifords 17a-(2-carboxyethyl)-6-methylandrost-5-ene-3p,1713-dio1 lactone as fine white needles melting at 152-154". The product has the formula Example 10 tinned for 30 minutes, whereupon the reaction mixture is cooled, diluted with approximately 150 parts of saturated aqueous Rochelle salt solution, and steam-distilled until the distillate comes over free of oil. The distillation residue is cooled, acidified to pH 2.0, and extracted withchloroform. The choloroform extract is stripped of solvent by distillation, leaving a glass which is taken up in parts of methanol. The methanol solution is diluted with 10 parts of 10% hydrochloric acid (to insure lactone formation). After 5 minutes, the solution is poured into 1000 parts of water; and the resultant mixture is extracted with ether. Evaporation of solvent leaves a light brown glass which is still further purified by chromatography on silica gel, using benzene and ethyl acetate as developing solvents. The 17a-(2-carboxyethyl)-17p-hydroxy-6a-methylandrost-4-en-3-one lactone thus obtained, on crystallization from a mixture of ethyl acetate and isopropyl ether, melts at approximately 149- 150. A 1% solution of the product in chloroform has a specific rotation of +64 and shows a maximum at 240 millimicrons in the ultraviolet spectrum, with a molar extinction coelficient of 16,570. The product has the formula CH: HsC

Example 11 17a (2 carboxyethyl) 6oz methylandrost 4 ene 3,8,17fi-di0l lactone-Using the technique of Example 7, but substituting 6 parts of 17a-(2-carboxyethyl)17fl.- hydroxy-6m-methylandrost-4 en-3-one lactone for the 6 parts of (2 carboxyethyl) l7B-hydroxy-6fi-methylandrost-4-en-3-one lactone called for therein, one obtains 17a (2 carboxyethyl) 60c methylandrost 4 ene 35,17B-diol lactone, 'the formula of which is Example 12 17c: (2 carboxyvinyl) 6 methylandrost 5 ene 33,1713 diol lactone-A solution of approximately 176 parts of 17a carboxyethynyl 6 methylandrost 5 ene 3 8,1713 diol in 4300 parts of dioxane containing 430 pants of pyridine is agitated with hydrogen at room ternperatures and atmospheric pressures in the presence of approximately 57 parts of 5% palladium supported on calcium carbonate. When 1 part of hydrogen has been absorbed, the reduction is stopped and the reaction mixture thereupon filtered to remove catalyst. The bulk of the solvent is stripped by vacuum distillation, and the oily residue is thoroughly mixed with 1900 parts of 10% hydrochloric acid. The solid product which results is filtered off and crystallized from a mixture of ethyl acetate and isopropyl ether. The 17u-(2-carboxyvinyD-6- 9 methylandrost ene 35,1713 diol lactone thus ob- CH: Haf

OH: Example 13 17a (2 carboxyvinyl) 17/3 hydraxy 6o: methylandrost 4 en 3 one lactone.-Substitution of 17a (2 carboxyvinyl) 6 methylandrost 5 ene 313,173 diol lactone for the 170: (2 carboxyethyl) 6 methylandrost 5 ene 3 3,175 diol lactone called for in Example 10 affords, by the procedure therein described, 170: (2 carboxyvinyl) 17;? hydroxy 6a methylandrost 4 en 3 one lactone, which has the formula T CH: H10

What is claimed is: 1. A compound of the formula wherein Z is selected from the group consisting of ethylene and vinylene radicals, and X is selected from the group consisting of carbonyl and fl-hydroxymethylene radicals.

2. A compound of the formula To on, mo

3. 17oz (2 carboxyethyl) 6B methyl 17p hydroxyandrost 4 en 3 one lactone.

4. 17a (2 carboxyethyl) 17 3 hydroxy 6a methylandrost 4 en 3 one lactone.

5. A compound of the formula References Cited in the file of this patent UNITED STATES PATENTS 2,705,712 Cella Apr. 5, 1955 

1. A COMPOUND OF THE FORMULA WHEREIN Z IS SELECTED FROM THE GROUP CONSISTING OF ETHYLENE AND VINYLENE RADICALS, AND X IS SELECTED FROM THE GROUP CONSISTING OF CARBONYL AND B-HYDROXYMETHYLENE RADICALS.
 8. 3B-ACETOXY-17A-(3-ACETOXYPROPYL) -5A,6AEPOXYANDROSTAN-17B-OL. 